11-Deoxyprostaglandin derivatives

ABSTRACT

A process for preparing 11-deoxyprostaglandin E 1 , E 2  and E 3  and analogs thereof is realized by treating an appropriate di(lower)alkyl 3-(optionally substituted)-2-formylcyclopropane-1,1-dicarboxylate with an ylid prepared from a Witting reagent of formula (AlkO) 2  POCH 2  CO-(c)-CH 3  in which Alk is an alkyl containing one to three carbon atoms and (c) is either (CH 2 ) q  wherein q is an integer from 1 to 6 or cis CH 2  CH═CH(CH 2 ) r  wherein r is an integer from 0 to 3 to obtain the corresponding compound of formula: ##STR1## in which R 2  is hydrogen, lower alkyl or CH 2  OR 3  wherein R 3  is lower alkanoyl, R 4  is lower alkyl and (c) is as defined herein. The latter compound is reduced with an alkali metal borohydride to yield the corresponding alcohol derivative. Condensation of this alcohol derivative or preferably its corresponding tetrahydropyran-2-yl ether derivative with a triester of formula CH(COOR 6 ) 2  -(a)-(CH 2 )pCOOR in which R and R 6  are lower alkyl, (a) is CH 2  CH 2 , cis CH═CH or C.tbd.C and p is an integer from 2 to 4, gives the corresponding cyclopentanonetriester of formula ##STR2## in which (a), (c), p, R, R 4  and R 6  are as defined herein, R 5  is hydrogen or tetrahydropyran-2-yl, respectively, and R 7  is hydrogen or lower alkyl; the lactonized form of the cyclopentanonetriester being obtained from said alcohol derivative in which R 2  is CH 2  OR 3  wherein R 3  is lower alkanoyl. In the instance when R 5  is tetrahydropyran-2-yl the cyclopentanonetriester is treated with an acid to give the corresponding compound in which R 5  is hydrogen. The instant compound is then treated with a base under aqueous conditions, followed by optional esterification and acylation to give the desired 11-deoxyprostaglandin derivatives of formula ##STR3## in which (a), (c) and p, are as defined herein, (b) is trans CH═CH, R is hydrogen or lower alkyl, R 1  is hydrogen or lower alkanoyl and R 2  is hydrogen, lower alkyl or CH 2  OR 3  wherein R 3  is hydrogen or lower alkanoyl. The derivatives possess prostaglandin-like biological activity and methods for their use are given.

This is a division, of application Ser. No. 489,856, filed July 19, 1974now U.S. Pat. No. 4,006,136, which is a divisional application of Ser.No. 238,650 filed Mar. 27, 1972, now U.S. Pat. No. 3,849,474.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to prostaglandin derivatives. More particularlythis invention relates to derivatives of 9,15-dioxygenated prostanoicacid and homologs thereof, to novel methods for producing thesederivatives and to novel chemical intermediates useful in these methods.

2. Description of the Prior Art

Prostaglandins are naturally occurring C-20 fatty acids. The basicprostaglandin molecule contains a cyclopentane nucleus with two sidechains. The chemistry and pharmacological effects of the prostaglandinshave been the subject of several recent reviews; for example, see E. W.Horton, Physiol. Rev., 49, 122 (1969), J. F. Bagli in "Annual Reports inMedicinal Chemistry, 1969", C. K. Cain, Ed., Academic Press, New Yorkand London, 1970, p. 170, and J. E. Pike in "Progress in the Chemistryof Organic Natural Products", Vol. 28, W. Herz, et al. Eds., SpringerVerlag, New York, 1970, p. 313.

The pharmacological effects known to be associated with theprostaglandins relate to the reproductive, cardiovascular, respiratory,gastrointestinal and renal systems.

Due to the increasing interest in these natural products a ratherextensive effort has been given recently to the synthesis ofprostaglandins and their analogs. Included among these synthesis areseveral synthetic methods for the preparation of 9,15-dioxygenatedderivatives of prostanoic or prost-13-enoic acids. For example, thesynthesis of the first pharmacologically active 9,15-dioxygenatedprostanoic acid derivative, 9ξ,15ξ-dihydroxyprost-13-enoic acid(11-desoxyprostaglandin F₁) was reported in detail by J. F. Bagli, T.Bogri and R. Deghenghi, Tetrahedron Letters, 465 (1966). A significantsimplification and modification of that process was described by Bagliand Bogri in U.S. Pat. No. 3,455,992, issued July 15, 1969, whereby9ξ,15ξ-dihydroxyprost-13-enoic acid as well as homologs thereof wereobtained, see also Bagli and Bogri, Tetrahedron Letters, 5 (1967)

A further improvement in the synthesis of 9,15-dioxygenated derivativesof prostanoic acid has been described by Bagli and Bogri in TetrahedronLetters, 1639 (1969), and German Offenlegungsschrift No. 1,953,232,published Apr. 30, 1970. This latter synthesis gave 9,15-dioxoprostanoicacid methyl ester and homologs thereof, from which a number of other9,15-dioxygenated derivatives of prostanoic acid and of homologs thereofwere prepared by conventional means.

A synthesis of 9,15-dioxygenated prostanoic and prost-13-enoic acidderivatives from 9,11,15-trioxygenated derivatives is reported inBritish Patent Specification No. 1,097,533, published January 3, 1968.Among the derivatives prepared by this synthesis are the compounds offormula I of this invention in which (a) is CH₂ CH₂, (b) is trans CH═CH,p is the interger 3, (c) is (CH₂)_(q) wherein q is the interger 4, R ishydrogen or lower alkyl and R¹ and R² are hydrogen.

It is particularly noteworthy that the synthetic 9,15-dioxygenatedprostanoic acid derivatives described above possess a number of thebiological activities of the natural compounds although they lack the11-hydroxyl of the latter.

Notwithstanding the fact that many of the syntheses reported to date areoutstanding achievements, it is the purpose the present invention toprovide an efficient, economical process that affords one or more of thefollowing advantages over the earlier processes: (a) simplicity ofoperation, (b) versatility of its application to the preparation of11-deoxy PGE₁, PGE₂ and PGE₃, analogs and 11-substituted derivativesthereof, (c) applicability to the preparation of higher and lowerhomologs thereof, and (d) the final products of this invention arereadily reduced by known methods to the corresponding derivatives in thePGF series.

The present invention relates to an entirely new approach for thesynthesis of 9,15-dioxygenated prostanoic acid derivatives which isunrelated to any of the above processes. The basis for this new approachis the unexpected discovery that an appropriately substituted dialkylcyclopropane-1,1-dicarboxylate derivative condenses with anappropriately substituted dialkyl malonate derivative to give thecorresponding cyclopentan-2-one-1,3-dicarboxylate derivative. Thelatter, upon appropriate transformations, thereafter is converted to thecompounds of this invention, viz., cyclopentan-1-ones suitablysubstituted at positions 2 and 3 in a trans relationship with carbonside chains bearing the functional groups and the requisite degree ofunsaturation analagous to the prostaglandin molecule, see the steps II +III→IV→I described hereinafter.

Although R. W. Kierstead et al., J. Chem. Soc., 3616 (1952) and R.Giuliano et al., Ann. Chim. (Rome), 50, 750 (1960), Chem. Abstr. 55,3463 (1961) previously have condensed cyclopropane-1,1-dicarboxylatederivatives with dialkyl malonate or substituted derivatives thereof,the process of the present invention is readily distinguished from theprior art because decarboxylation of the intermediate tricarboxylateobtained by the process of this invention gives 2,3-disubstitutedcyclopentan-1-one derivatives in which the side chains attached intrans-relationship to position 2 to 3 both carry functional groups,while the processes of the prior art were not capable of allowing theintroduction of such side chains.

SUMMARY OF THE INVENTION

The prostaglandin derivatives of this invention may be represented bygeneral formula I: ##STR4## in which (a) is CH₂ CH₂, cis CH═CH or C═C, pis an interger from 2 to 4, (b) is trans CH═CH, (c) is either (CH₂)_(q)wherein q is an interger from 1 to 6 or cis CH₂ CH═CH(CH₂)_(r) wherein ris an integer from 0 to 3, R is hydrogen or lower alkyl, R¹ is hydrogenor lower alkanoyl and R² is hydrogen, lower alkyl or CH₂ OR³ wherein R³is hydrogen or lower alkanoyl, provided that R¹ is the same as R³.

The prostaglandin derivatives of this invention may be prepared by aprocess involving a series of key steps which are representedschematically in the following manner: ##STR5## in which (a), (c) and pare as defined hereinbefore, R is lower alkyl, R² is hydrogen, loweralkyl or CH₂ OR³ in which R³ is lower alkanoyl, R⁴ is lower alkyl and R⁵is hydrogen or a radical suitable for protecting a hydroxyl, preferablytetrahydropyran-2-yl or tertbutyl, R⁶ is lower alkyl and R⁷ is hydrogenor lower alkyl.

In the preceding process the compound of formula II is subjected to abase catalyzed condensation with the triester of formula III to yieldthe cyclopentanonetriester of formulae IVa or IVb. The lactonized formof the cyclopentanonetriester, compound IVb, is obtained in this processwhen R² of compound II is CH₂ OR³ wherein R³ is lower alkanoyl. In theinstance when R⁵ of the cyclopentanonetriester of formula IVa or IVb isa protecting radical, as defined hereinbefore, saidcyclopentanonetriester is then treated with a suitable acid to removethe protecting radical whereby the corresponding cyclopentanonetriesterof formulae IVa or IVb in which R⁵ is H is obtained. The instantintermediate of formulae IVa or IVb is then treated with a base underaqueous conditions to give the corresponding compound of formula I inwhich R is hydrogen. Thereafter and if desired the latter compound isesterified to give the corresponding compound of formula I in which R islower alkyl and if desired said latter compounds of formula I in which Ris hydrogen or lower alkyl is acylated to give the correspondingcompound of formula I in which R¹ and R³ are lower alkanoyl.

According to a further feature of this invention a process for thepreparation of compounds of formula II comprises the treatment of analdehyde of formula V ##STR6## in which R² is hydrogen, lower alkyl orCH₂ OR³ in which R³ is lower alkanoyl and R⁴ is lower alkyl, with anylid prepared from a Wittig reagent of formula (AlkO)₂ POCH₂ CO-(c)-CH₃in which (c) is as defined in the first instance and Alk is an alkylcontaining one to three carbons, in the presence of a suitable base toobtain a compound of formula VI ##STR7## in which R², R⁴ and (c) are asdefined above, reducing the latter compound with an alkali metalborohydride to obtain the compounds of formula II in which R⁵ ishydrogen and if desired converting the latter compound to thecorresponding compounds of formula II in which R⁵ is a radical suitablefor protecting a hydroxyl, preferably a tetrahydropyran-2-yl.

Still another feature of this invention is that the process describedherein leads to the compounds of formula I in which the two side chainsare in the trans configuration characteristic for the naturalprostaglandins.

DETAILS OF THE INVENTION

The term "lower alkyl" as used herein contemplates straight or branchedchain alkyl groups containing from one to three carbon atoms andstraight alkyl chains containing from four to six carbon atoms andincludes methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.

The term "lower alkanoyl" as used herein contemplates straight orbranched chain alkanoyl radicals containing from two to five carbonatoms and includes acetyl, propionyl, butyryl, isobutyryl, pentanoyl andpivaloyl.

The compound of formula I possess interesting pharmacological propertieswhen tested in standard pharmacological tests. In particular, they havebeen found to possess hypotensive, antihypertensive, bronchospasmolytic,and gastric acid secretion inhibiting properties, which make them usefulin the treatment of conditions associated with high blood pressure, inthe treatment of asthmatic conditions and in the treatment ofpathological conditions associated with excessive secretion of gastricacid such as, for example peptic ulcer. In addition, the compound ofthis invention inhibit the aggregation of platelets and promote thedisaggregation of aggregated platelets, and are useful as agents for theprevention and treatment of thrombosis.

More particularly, these compounds, when tested in a modification of thetests for determining hypotensive activities described in "ScreeningMethods in Pharmacology", Academic Press, New York and London 1965, page146, using the cat in urethane-chloralose anaesthesia as the test animaland measuring mean arterial blood pressure before and after intravenousadministration of the compounds, have exhibited utility as hypotensiveagents. When tested in the renal hypertensive rat prepared by the methodof A. Grollman described in Proc. Soc. Exp. Biol. Med., 7, 102 (1954),and measuring blood pressure by the method described by H. Kersten, J.Lab. Clin. Med., 32, 1090 (1947), they have exhibited utility asantihypertensive agents.

Moreover, the compounds of this invention, when tested in a modificationof the test method described by A. K. Armitage, et al., Brit. J.Pharmacol., 16, 59 (1961), have been found to alleviate bronchospasms,and are useful as bronchospasmolytic agents.

Furthermore, the compounds of this invention, when administered to ratsin the test method described by H. Shay, et al., Gastroenternol., 26,906 (1954), have been found to inhibit the secretion of gastric acid,and are useful as agents inhibiting the secretion of gastric acid.

In addition, the compounds of this invention, when tested in amodification of the test method described by G. V. R. Born, Nature, 194,927 (1962), using the aggregometer manufactured by Bryston ManufacturingLimited, Rexdale, Ontario, Canada, have been shown to inhibit theaggregation of platelets and to promote the disaggregation of aggregatedplatelets, and are useful as agents for the prevention and treatment ofthrombosis.

When the compounds of this invention are employed as hypotensive oranti-hypertensive agents, as agents inhibiting gastric acid secretion inwarm-blooded animals, for example, in cats or rats, as agents for theprevention or treatment of thrombosis, or as bronchospasmolytic agents,alone or in combination with pharmacologically acceptable carriers,their proportions are determine by their solubilities, by the chosenroute of administration, and by standard biological practice. Thecompounds of this invention may be administered orally in solid formcontaining such excipients as starch, lactose, sucrose, certain types ofclay, and flavouring and coating agents. However, they are preferablyadministered parenterally in the form of sterile solutions thereof whichmay also contain other solutes, for example, sufficient sodium chlorideor glucose to make the solution isotonic. For use as bronchospasmolyticagents, the compounds of this invention are preferably administered asaerosols.

The dosages of the present hypotensive, antihypertensive, gastric acidsecretion inhibiting, or bronchospasmolytic agents, or agents for theprevention and treatment of thrombosis will vary with the forms ofadministration and the particular hosts under treatment. Generally,treatments are initiated with small dosages substantially less than theoptimum doses of the compounds. Thereafter, the dosages are increased bysmall increments until the optimum effects under the circumstances arereached. In general, the compounds of this invention are most desirablyadministered at a concentration level that will generally affordeffective results without causing any harmful or deleterious sideeffects and preferably at a level that is in a range of from about 0.1mg. to about 10.0 mg. per kilo, although as aforementioned variationswill occur. However, a dosage level that is in range of from about 0.5mg. to about 5 mg. per kilo is most desirably employed in order toachieve effective results. When administering the compounds of thisinvention as aerosols the liquid to be nebulized, for example, water,ethyl alcohol, dichlorotetrafluoroethane and dichlorodifluoromethane,contains preferably from 0.005 - 0.05 percent of the acid, or anon-toxic alkali metal, ammonium or amine salt thereof, or ester offormula I.

Furthermore, when the compounds of this invention are tested by themethod of A. P. Labhsetwar, Nature, 230, 588 (1971) whereby the compoundis given subcutaneously on a daily basis to mated hamsters on days 4,5and 6 of pregnancy, thereafter the animals being sacrificed on day 7 ofpregnancy and the number of abortions counted, the compounds are shownto have abortifacient properties. Also the compounds of this inventionare useful for inducing labor in pregnant animals at or near term. Whenthe compounds of this invention are employed as agents for abortion orfor inducing labor, the compound may be infused intravenously at a dose0.01 to 500 mg./kg. per minute until the desired effect is obtained.

PROCESS

As noted hereinbefore the preparation of the compounds of this inventioninvolve the base catalyzed condensation of a compound of formula II inwhich (c), R⁴ and R⁵ are as defined in the first instance and R² ishydrogen, lower alkyl, or CH₂ OR³ in which R³ is lower alkanoyl with atriester of formula III in which (a) and p are as defined in the firstinstance and R is lower alkyl.

The compound of formula II for this key reaction prepared as follows:

A di(lower)alkylbromomalonate, for example, dimethylbromomalonate,prepared by using the procedure for diethyl bromomalonate, "OrganicSyntheses", Collect. Vol. 1, 2nd ed., A. H. Blatt, Ed, John Wiley &Sons, New York, N.Y., 1956, p. 245, is condensed in the presence of analkali metal lower alkoxide in a lower alkanol, preferably sodiummethoxide in methanol, with acrolein; an α,β-unsaturated aldehyde offormula (lower alkyl)-CH═CH-CHO (see "Rodd's Chemistry of the CarbonCompounds", S. Coffey, Ed., Vol. 1c, 2nd Ed. pp. 48 - 51), for example,crotonaldehyde, 2-hexenal, and the like; or a γ-(loweralkanoyloxy)crotonaldehyde, preferably γ-acetoxycrotonaldehyde (preparedby treating γ-acetoxycrotonaldehyde diacetate, H. Schmid and E. Grob,Helv. Chim. Acta, 32, 77 (1949), with one equivalent of water in a loweralkanol); to yield a cyclopropanealdehyde derivative of formula V, i.e.,a di(lower)alkyl 2-formylcyclopropane-1,1-dicarboxylate, thecorresponding 3-lower alkyl analog or the corresponding 3-(loweralkanoyloxymethyl) analog, respectively. The reaction conditionsdescribed by D. T. Warner, J. Organic Chemistry, 24, 1536 (1959) for thepreparation of the cyclopropanealdehyde derivatives, diethyl 2-formylcyclopropane-1,1-dicaroxylate and its corresponding 3-methyl analog, areconvenient and quite satisfactory for this condensation.

The cyclopropanealdehyde derivative of formula V so obtained is thentreated with the ylid prepared from a Wittig reagent, of the formula(AlkO)₂ P(O)CH₂ CO-(c)-CH₃ in which (c) is as defined hereinbefore, andAlk is an alkyl containing from 1 to 3 carbon atoms, preferably adimethyl 2-oxoalkylphosphate, in the presence of an alkali metalhydride, preferably sodium hydride, and in an aprotic solvent,preferably dimethyoxyethane. Acidification with an aqueous acid,preferably aqueous acetic acid, extraction with a water - immisciblesolvent, preferably diethyl ether, followed by washing, drying andevaporation of the latter, yields the corresponding compound of formulaVI in which R² is hydrogen, lower alkyl or CH₂ OR³ in which R³ is loweralkanoyloxy.

The requisite Wittig reagents are either known, for example, dimethyl2-oxoheptylphosphonate, E. J. Corey, et al., J. Am. Chem. Soc., 90, 3247(1968) or they may be prepared by the method of E. J. Corey and G. T.Kwiatkowski, J. Am. Chem. Soc., 88, 5654 (1966) using the appropriatelower alkyl alkanoate or lower alkyl alkenoate and di(lower)alkylα-lithiomethanephosphonate.

More specifically, the treatment of the cyclopropanealdehyde derivativeof formula V with the ylid is performed in the following manner. Asolution of the Wittig reagent in about 5 to 10 parts of an aproticsolvent, preferably dimethoxyethane, is added slowly under a blanket ofnitrogen to a stirred suspension of approximately one equivalent of analkali metal hydride, preferably sodium hydride, in approximately 150parts of the aprotic solvent and stirring is continued at roomtemperature for a period of time of from 10 to 60 minutes, preferablyfor about 30 minutes. To the resulting solution of the correspondingylid there is slowly added a solution of approximately three quarters toone equivalent, preferably about 0.85 equivalent, of the appropriatecyclopropanealdehyde derivative described above in about 5 - 10 parts,preferably about 8 parts of an aprotic solvent, preferablydimethoxyethane. The addition is carried out at room temperature over aperiod of time of from 5 to 30 minutes, preferably about 10 minutes, andstirring is continued for another 10 to 60 minutes, preferably for about30 minutes. Acidification with an aqueous acid, preferably aqueousacetic acid, followed by extraction with a water - immiscible solvent,preferably diethyl ether, washing and drying of the extracts,evaporation of the solvent, and chromatography of the residue on silicagel yields the corresponding compound of formula VI in which (c) is asdefined hereinbefore, R² is hydrogen, lower alkyl or CH₂ OR³ wherein R³is lower alkanoyloxy and R⁴ is lower alkyl.

As an alternative to the above preferred procedure, the compounds offormula VI in which R² is hydrogen and (c) is (CH₂)_(q) wherein q is aninteger from 1 to 6 are prepared in the following manner: A chlorovinylketone of formula ClCH═CHCO(CH₂)_(n) CH₃ in which n is an integer from 1to 6, prepared by the general procedure described for the preparation of1-chloro-6-methyl-1-hepten-3-one in Organic Syntheses, 32, 27 (1952), isconverted to its corresponding di(lower)alkylaminovinyl ketone bytreatment with an excess, for example two to five molar equivalents, ofa di(lower)alkylamine, preferably 40% aqueous dimethylamine at roomtemperature for 20 minutes. The aminovinyl ketone is then reacted with avinyl magnesium halide, preferably vinyl magnesium bromide, in an inertsolvent, preferably dry tetrahydrofuran or ether. Preferred conditionsfor this reaction include a temperature range from room temperature tothe boiling point of the mixture and a reaction time of 30 minutes to 4hours. In this manner the dienone of formula CH₂ ═CHCH═CHCO(CH₂)_(n) CH₃in which n is an integer from 1 to 6 is obtained.

The same dienone is obtained also by treating the aminovinyl ketone,described above with lithium acetylide or an acetylene Grignard reagent,for example, ethynyl magnesium bromide or preferably lithiumacetylide-ethylenediamine complex, in an inert solvent, preferablydioxane, under essentially the same conditions described above for thereaction of a vinyl magnesium halide whereby said aminovinyl ketoneyields a compound of formula (lower alkyl)₂ NCH(C.tbd.CH)CH₂ CO(CH₂)_(n)CH₃ in which n is an integer from 1 to 6. Treatment of the lattercompound with an excess of acid, for example, 1.2 to 2.5 molarequivalents of hydrochloric, sulfuric or preferably p-toluenesulfonicacid, in an inert solvent, for example, methanol or tetrahydrofuran, toeffect the elimination of one molecule of di(lower)alkyl amine, followedby hydrogenation of the corresponding alkenynone product of formulaHC.tbd.CCH═CHCO(CH₂)_(n) CH₃ in which n is as described above, obtainedtherefrom, in the presence of Lindlar catalyst affords the dienone offormula CH₂ ═CHCH═CHCO(CH₂)_(n) CH₃ described above.

The latter dienone is now treated with a di(lower)alkyl bromomalonate,described above, in the presence of an alkali metal lower alkoxide toyield the desired compound of formula VI in which R² is hydrogen, R⁴ islower alkyl and (c) is (CH₂)_(q) wherein q is an integer from 1 to 6.More specifically this reaction is effected by adding simultaneously asolution of the dienone in a lower alkanol, for example, ethanol, and asolution of about one equivalent of an alkali metal lower alkoxide, forexample, sodium ethoxide, in the same lower alkanol as above, to anagitated solution of approximately one equivalent of the di(lower)alkylbromomalonate, for example, diethyl bromomalonate, in the same loweralkanol described above. The temperature during addition may range from-20° to 60° C., preferably 0° to 20° C. After completion of theaddition, the mixture is stirred for about three hours at the sametemperature then at room temperature for a further 8 to 24 hours.Thereafter the mixture is neutralized with acid, preferably acetic acid,the precipitated alkali metal bromide separated by filtration, and thereaction mixture concentrated. The residue is purified on silica gel toyield the desired compound of formula VI.

Thereafter, the compound of formula VI in which (c) is as defined in thefirst instance, R² is hydrogen, lower alkyl or CH₂ OR³ wherein R³ islower alkanoyloxy and R⁴ is lower alkyl is reduced with an alkali metalborohydride, potassium borohydride or preferably sodium borohydride, inan inert solvent to yield a mixture of epimers of the desired compoundof formula II in which R⁵ is hydrogen. The epimers result from theassymetric center at the carbon to which the secondary alcohol isattached. The mixture of epimers need not be separated at this stage. Inpractice it has been found more convenient to continue the process withthe mixture of epimers and if desired separate the resulting epimers ofcompounds of formula I.

Thereafter and if desired, the compound of formula II in which R⁵ ishydrogen is converted to the corresponding compound of formula II inwhich R⁵ is a radical suitable for protecting a hydroxyl, preferably atetrahydropyran-2-yl which is readily formed by treating said lattercompound with dihydropyran in the presence of an acid catalyst; forinstance, p-toluenesulfonic acid is preferred. Sulfuric acid is also asuitable catalyst for this purpose.

The triester of formula III for the above key reaction is prepared inthe following manner:

The triester of formula III in which (a) is C .tbd. C, noted above, isprepared by a process which is represented schematically in thefollowing manner: ##STR8## in which p is as defined in the firstinstance and R is lower alkyl.

With reference to the preceding process propargyl alcoholtetrahydropyran-2-yl ether, described by R. G. Jones and M. J. Mann, J.Amer. Chem. Soc., 75, 4048 (1953), is condensed with a dihaloalkane offormula VIII to give the tetrahydropyranyl ether of formula IX accordingto the procedure of A. I. Rachlin, et al., J. Org. Chem., 26, 2688(1961), used to prepare 1-[(tetrahydropyran-2-yl)oxy]-6-chloro-2-hexyne.The tetrahydropyranyl ether of formula IX is hydrolyzed, for example,with p-toluenesulfonic acid in aqueous methanol, to its correspondingalcohol of formula X, see also the procedure of Rachlin, cited above,for the preparation of 6-chloro-2-hexyn-1-ol (X, p = 3). The alcohol Xis then treated with potassium or sodium cyanide in a lower alkanol,preferably with potassium cyanide in ethanol, at reflux temperature foreight to 24 hours to give the cyanide XI. Subsequently a solutioncontaining an excess of potassium hydroxide in water is added to thereaction mixture of the cyanide XI and the resultant mixture is heatedat reflux for a further 10 to 20 hours whereby the cyanide XI isconverted to the corresponding hydroxyacid XII. The latter compound isthen brominated by treatment with phosphorus tribromide in ethersolution in the presence of a suitable proton acceptor, for example,pyridine, to yield the corresponding bromoacid XIII, which is esterifiedwith a lower alkanol, for example, methanol in the presence of asuitable acid catalyst, for example, p-toluenesulfonic acid, to give thecorresponding bromoester of formula XV.

Alternatively, the order of the latter two steps of bromination andesterification are reversed whereby the hydroxyacid XII is converted tothe bromoester of formula XV via the hydroxy ester XIV.

Optionally, the corresponding chloroester of the bromoester of formulaXV is prepared by the preceding process by replacing the dihaloalkane offormula VIII with its corresponding α-iodo-(ω)-chloroalkane. Thechloroester so obtained is used in the same manner as described hereinfor said bromoester.

Thereafter the desired triester of formula III in which (a) is C.tbd.Cis obtained by condensing the above bromoester of formula XV with adialkylmalonate, in the presence of an alkali metal alkoxide in a loweralkanol. More particularly, the condensation is performed by adding thedialkylmalonate portionwise to a solution of one equivalent of sodiummethoxide in methanol at a temperature of from 10° to 30° C., preferablyroom temperature. After stirring for about 10 to 20 minutes, thereaction mixture is treated portionwise with one equivalent of thebromoester of formula XV followed by heating the reaction mixture atreflux temperature for one to two hours. Thereafter, dilution of themixture with water, extraction with a water-immiscible solvent,preferably ether, washing and drying of the extract, followed by removalof the solvent gives a residue, which on purification by distillationunder reduced pressure gives the desired triester III in which (a) isC.tbd.C.

The triesters of formula III in which (a) is cis CH═CH or CH₂ CH₂ areprepared by condensing the appropriate lower alkyl ω-haloalkanoate witha dialkylmalonate in the same manner as just described for thepreparation of triester III in which (a) is C.tbd.C. The appropriatelower alkyl ω-haloalkanates, for this condensation are either known orare prepared by known methods; for example, by hydrogenation of thebromoesters of formula XV or its corresponding chloroester, see also"Rodd's Chemistry of the Carbon Compounds", cited above, Vol. 1c, pp.201 - 252.

Alternatively, the triester of formula III in which (a) is cis CH═CH isprepared by hydrogenation of the corresponding triester of formula IIIin which (a) is C.tbd.C, described above, in the presence of Lindlarcatalyst.

The compound of formula II and the triester of formula III, prepared asdescribed above, are now subjected to a base catalyzed condensation togive the cyclopentanonetriester of formulae IVa and IVb. Morespecifically, the condensation is performed in the presence of suitablebase, preferably an alkali metal alkoxide, for example, sodiummethoxide. Other suitable bases include sodium ethoxide, potassiumtert-butoxide, and sodium hydride. In particular, this condensation maybe conveniently effected by heating a mixture of about equimolar amountsof the compound of formula II and the triester III at 100° to 150° C.,preferably 135° - 140° C., for 30 minutes to three hours, preferably onehour. The reaction mixture is then cooled, treated with saturated sodiumchloride solution neutralized with an acid, for example, acetic acid,and extracted with a water-immiscible solvent, for example, ether.Evaporation of the extract and purification of the residue bychromatography on silica gel yields the cyclopentanonetriester offormulae IVa or IVb.

Although compounds of formula II in which R⁵ is either hydrogen or aprotecting radical as defined above undergo the above base catalyzedcondensation, it is preferable to use those compounds of formula IIhaving the protecting group. In the latter case following thecondensation the protecting group is then removed. More explicitly in apreferred embodiment the base catalyzed condensation is effected with acompound in which R⁵ is tetrahydropyran-2-yl and thereafter thetetrahydropyran-2-yl protecting group is removed by treating theresulting cyclopentanonetriester of formula IV (R⁵ ═tetrahydropyran-2-yl) with acid, for example, hydrochloric acid, aqueousacetic acid or preferably p-toluenesulfonic acid, in an inert solvent inthe presence of water, preferably methanol-water (9:1).

The cyclopentanonetriester (IVa or IVb) is now treated with an alkalimetal hydroxide under aqueous conditions to give the compounds offormula I in which (a), (b), (c) and p are as defined in the firstinstance, R and R¹ are hydrogen and R² is hydrogen, lower alkyl or CH₂OR³ wherein R³ is hydrogen. Preferably this reaction is done by heatinga mixture of the cyclopentanonetriester with an alkali metal hydroxide,preferably sodium hydroxide or potassium hydroxide, under aqueousconditions at reflux temperature of the mixture for a period of 15minutes to three hours, preferably about one hour. Neutralization of thereaction mixture with acid, for example, 2N HCl, extraction with awater-immiscible solvent, for example, ether, and subsequent work up ofthe extract yields a mixture of epimers of compounds of formula I inwhich R and R¹ are hydrogen and R² is hydrogen, lower alkyl or CH₂ OR³wherein R³ is hydrogen. If desired the epimers may be convenientlyseparated at this stage by chromatography on silica gel. For conveniencethe less polar epimer is designated epimer A and the more polar, epimerB.

Thereafter and if desired the latter compounds are esterified with alower alkanol, for example, methanol, ethanol or propanol, in thepresence of a acid, for example, sulfuric acid, hydrochloric acid orpreferably perchloric acid, to give the corresponding ester compounds offormula I in which (a), (b), (c) and p are as defined in the firstinstance, R is lower alkyl, R¹ is hydrogen and R² is hydrogen, loweralkyl or CH₂ OR³ wherein R³ is hydrogen.

Within this latter group of compounds of formula I is the compound,9-oxo-15-hydroxyprost-13-enoic acid methyl ester (I; (a) ═ CH₂ CH₂, (b)═ trans CH═CH, p ═ 3, (c) is (CH₂)_(q) wherein q is the integer 4, R ismethyl, R¹ and R² ═ H). By means of spectroscopic evidence thisparticular prostaglandin derivative has been shown to be identical withthe same compound described in British Patent Specification No.1,097,533, noted above.

Finally, if desired the above compounds of formula I in which R ishydrogen or lower alkyl are acylated by treatment with an appropriatelower alkanoic anhydride or lower alkanoic acid chloride in the presenceof pyridine to give the corresponding compounds of formula I in which(a), (b), (c) and p are as defined in the first instance R is hydrogenor lower alkyl, R¹ is lower alkanoyl and R² is hydrogen, lower alkyl orCH₂ OR³ wherein R³ is lower alkanoyl.

The following examples illustrate further this invention.

EXAMPLE 1 Dimethyl 2-Formylcyclopropane-1,1-dicarboxylate (V, R² ═ H andR⁴ ═ CH₃)

By following the procedure of D. T. Warner, cited above, used forpreparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acroleinbut using equivalent amount of dimethylbromomalonate and methanolinstead of diethylbromomalonate and ethanol, respectively, the titlecompound, nmr (CDCl₃) δ 1.98 (m,2H), 2.80(m, 1H), 3.79(s,6H), 8.82(d, J═ 4 cps, 1H), is obtained.

In the same manner but replacing acrolein with an equivalent amount ofcrotonaldehyde,

2-pentenal, 2-hexenal or γ-acetoxycrotonaldehyde, the followingcompounds of formula V,

dimethyl 2-formyl-3-methylcyclopropane-1,1-dicarboxylate,

dimethyl 2-formyl-3-ethylcyclopropane-1,1-dicarboxylate,

dimethyl 2-formyl-3-propylcyclopropane-1,1-dicarboxylate,

dimethyl 3-(acetoxymethyl)-2-formylcyclopropane-1,1-dicarboxylate areobtained, respectively.

Likewise the corresponding diethyl and dipropyl esters of the abovecompounds of formula V are obtained by the choice of appropriatestarting materials. For example, by using diethylbromomalonate, ethanoland γ-acetoxycrotonaldehyde, diethyl3-(acetoxymethyl)-2-formylcyclopropane-1,1-dicarboxylate, γ_(max)^(film) 2730, 1730 cm⁻¹, is obtained.

γ-Acetoxycrotonaldehyde is prepared by treating γ-acetoxycrotonaldehydediacetate, H. Schmid and E. Grob, Helv. Chem. Acta, 32, 77 (1949), withone equivalent of water in a lower alkanol, for example, ethanol.

EXAMPLE 2 Dimethyltrans-2-(3-Oxo-1-octenyl)cyclopropane-1,1-dicarboxylate [VI, R² ═ H, R⁴═ CH₃ and (c) ═ (CH₂)₄ ]

To 5.56 g of a 50% sodium hydride (NaH) suspension, rinsed with dryhexane, suspended in 400 ml dry 1,2-dimethoxyethane is added 27.4 g ofthe Wittig reagent, dimethyl-(2-oxoheptyl)phosphonate, in 400 ml dry1,2-dimethoxyethane. The reaction mixture is stirred at room temperaturetill all NaH reacts to give the sodium salt (about 45 minutes). Asolution of 21.6 g of dimethyl 2-formylcyclopropane-1,1-dicarboxylate(V, R² ═ H and R⁴ ═ CH₃), described in Example 1, in 350 ml dry1,2-dimethoxyethane is added and the mixture is heated at 60° C for 1/2hr; cooled, and acetic acid is added to render the mixture substantiallyneutral. After diluting with water the mixture is extracted with ether.The extract is washed with water, dried (MgSO₄) and evaporated. Theresidue is purified by chromatography on silica gel to yield the titlecompound, nmr (CDCl₃) δ 0.88(t,3H), 1.77(m,2H), 3.77(s,3H).

By following the procedure of Example 2 and utilizing the appropriateWittig reagent and compound of formula V then other compounds of formulaVI are prepared. Examples of such compounds of formula V are listed inTable I together with the appropriate Wittig reagent and compound offormula V utilized for their preparation.

                                      TABLE I                                     __________________________________________________________________________        WITTIG REAGENT COMPOUND OF                                                   (Alko).sub.2 P(O)CH.sub.2 CO-(c)-CH.sub.3                                                     FORMULA V PRODUCT: (PREFIX LISTED BELOW)                   EX.                                                                              Alk  (c)        R.sup.2                                                                            R.sup.4                                                                            CYCLOPROPANE-1,1-DICARBOXYLATE                   __________________________________________________________________________     3 CH.sub.3                                                                          CH.sub.2    H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1-pentenyl)               4 CH.sub.3                                                                          (CH.sub.2).sub.4                                                                          H    C.sub.2 H.sub.5                                                                    diethyl trans-2-(3-oxo-1-octenyl)                 5 CH.sub.3                                                                          (CH.sub.2).sub.3                                                                          H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1-heptenyl)               6 CH.sub.3                                                                          (CH.sub.2).sub.5                                                                          H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1-nonenyl)                7 CH.sub.3                                                                          (CH.sub.2).sub.6                                                                          H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1-decenyl)                8 CH.sub.3                                                                          CH.sub.2 CH═CH                                                                        H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1,5-hepta-                                            dienyl)                                           9 CH.sub.3                                                                          CH.sub.2 CH═CHCH.sub.2                                                                H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1,5-octa-                                             dienyl)                                          10 CH.sub.3                                                                          CH.sub.2 CH═CH(CH.sub.2).sub.2                                                        H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1,5-nona-                                             dienyl)                                          11 CH.sub.3                                                                          CH.sub.2 CH═CH(CH.sub.2).sub.3                                                        H    CH.sub.3                                                                           dimethyl trans-2-(3-oxo-1,5-deca-                                             dienyl)                                          12 CH.sub.3                                                                          CH.sub.2    CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1-pentenyl)                                      13 CH.sub.3                                                                          (CH.sub.2).sub.2                                                                          CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1-hexenyl)                                       14 CH.sub.3                                                                          (CH.sub.2).sub.3                                                                          CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1-heptenyl)                                      15 CH.sub.3                                                                          (CH.sub.2).sub.4                                                                          CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1-octenyl)                                       16 CH.sub.3                                                                          (CH.sub.2).sub.5                                                                          CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1-nonenyl)                                       17 CH.sub.3                                                                          (CH.sub.2).sub.6                                                                          CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1-decenyl)                                       18 CH.sub.3                                                                          CH.sub.2 CH═CH                                                                        CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1,5-heptadienyl)                                 19 CH.sub.3                                                                          CH.sub.2 CH═CHCH.sub.2                                                                CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo-                                             1,5-octadienyl)                                  20 CH.sub.3                                                                          CH.sub.2 CH═CH(CH.sub.2).sub.2                                                        CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-)3-oxo-                                             1,5-nonadienyl)                                  21 CH.sub.3                                                                          CH.sub.2 CH═CH(CH.sub.2).sub.3                                                        CH.sub.3                                                                           CH.sub.3                                                                           dimethyl trans-3-methyl-2-(3-oxo)-                                            1,5-decadienyl)                                  22 CH.sub.3                                                                          CH.sub.2    C.sub. 2 H.sub.5                                                                   CH.sub.3                                                                           dimethyl trans-3-ethyl-2-(3-oxo-                                              1-pentenyl)                                      23 CH.sub.3                                                                          (CH.sub.2).sub.4                                                                          C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    diethyl trans-3-ethyl-2-(3-oxo-                                               1-octenyl)                                       24 CH.sub.3                                                                          (CH.sub.2).sub.6                                                                          C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           dimethyl trans-3-ethyl-2-(3-oxo-                                              1-decenyl)                                       25 C.sub.2 H.sub.5                                                                   CH.sub.2 CH═CH                                                                        C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    diethyl trans-3-ethyl-2-(3-oxo-                                               1,5-heptadienyl)                                 26 C.sub.2 H.sub.5                                                                   CH.sub.2 CH═CHCH.sub.2                                                                C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                    diethyl trans-3-ethyl-2-(3-oxo-                                               1;5-octadienyl)                                  27 CH.sub.3                                                                          (CH.sub.2).sub.2                                                                          n-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           dimethyl trans-3-propyl-2-(3-oxo-                                             1-hexenyl)                                       28 CH.sub.3                                                                          (CH.sub.2).sub.4                                                                          n-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           dimethyl trans-3-propyl-2-(3-oxo-                                             1-octenyl)                                       29 CH.sub.3                                                                          (CH.sub.2).sub.5                                                                          i-C.sub.3 H.sub.7                                                                  C.sub.2 H.sub.5                                                                    diethyl trans-3-isopropyl-2-(3-oxo-                                           1-nonenyl)                                       30 C.sub.2 H.sub.5                                                                   CH.sub.2 CH═CH(CH.sub.2).sub.2                                                        i-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           dimethyl trans-3-isopropyl-2-(3-oxo-                                          1,5-nonedienyl)                                  31 C.sub.2 H.sub.6                                                                   CH.sub.2 CH═CH(CH.sub.2).sub.3                                                        n-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           dimethyl trans-3-propyl-2-(3-oxo-                                             1,5-decadienyl)                                  32 CH.sub.3                                                                          (CH.sub.2).sub.3                                                                          AcOCH.sub.2                                                                        CH.sub.3                                                                           dimethyl trans-3-(acetoxymethyl)-2-                                           (3-oxo-1-heptenyl)                               33 CH.sub.3                                                                          (CH.sub.2).sub.4                                                                          AcOCH.sub.2                                                                        C.sub.2 H.sub.5                                                                    diethyl trans-3-(acetoxymethyl)-2-                                            (3-oxo-1-octenyl),δ.sub.max.sup.film                                    1730,1690,                                                                    1670, 1625 cm.sup.-1                             34 CH.sub.3                                                                          (CH.sub.2).sub.6                                                                          AcOCH.sub.2                                                                        C.sub.2 H.sub.5                                                                    diethyl trans-3-(acetoxymethyl)-2-                                            (3-oxo-1-decenyl)                                35 CH.sub.3                                                                          CH.sub.2 CH═CH                                                                        AcOCH.sub.2                                                                        C.sub.2 H.sub.5                                                                    diethyl trans-3-(acetoxymethyl)-                                              2-(3-oxo-1,5-heptadienyl)                        36 CH.sub.3                                                                          CH.sub.2 CH═CHCH.sub.2                                                                AcOCH.sub.2                                                                        C.sub.2 H.sub.5                                                                    diethyl trans-3-(acetoxymethyl)-                                              2-(3-oxo-1,5-octadienyl)                         __________________________________________________________________________

EXAMPLE 37 1-(Dimethylamino)-1-octen-3-one

A solution of dimethylamine (560 ml, 40% aqueous) is cooled to 5° C.1-Chloro-1-octen-3-one (192 g) is added and the mixture stirred at roomtemperature for 20 min. The solution is then saturated with potassiumcarbonate and extracted with ether. The organic layer is washed 3 x withsat. sodium chloride solution, dried over sodium sulfate, concentratedand distilled to give the title compound, b.p. 94°-96° C/0.2mm.

In the same manner but replacing 1-chloro-1-octen-3-one with anequivalent amount of 1-chloro-1-penten-3-one, 1-chloro-1-hexen-3-one,1-chloro-1-hepten-3-one, 1-chloro-1-nonen-3-one or1-chloro-1-decen-3-one, then 1-(dimethylamino)-1-penten-3-one,1-(dimethylamino)-1-hexen-3-one, 1-(dimethylamino)-1-hepten-3-one,1-(dimethylamino)-1-nonen-3-one and 1-(dimethylamino)-1-decen-3-one areobtained, respectively.

EXAMPLE 38 1,3-Decadien-5-one

To a solution of Grignard reagent prepared from vinyl bromide (10.7 g),and magnesium (2.43 g) in dry tetrahydrofuran (40 ml) is added graduallya solution of 1-(dimethylamino)-1-octen-3-one (16.9 g), described inExample 37, in dry tetrahydrofuran (20 ml). The mixture is stirred andheated to reflux for 1 hr. The reaction mixture is cooled to roomtemperature, diluted with ether, washed with hydrochloric acid (10 ml),followed by saturated ammonium chloride solution. The ether extract isdried, and the solvent is removed. The residue is chromatographed toyield the title compound, λ_(max) ^(EtOH) 260nm (ε = 17,050), γ_(max)^(film) 1686, 1668 cm⁻¹.

In the same manner but replacing 1-(dimethylamino)-1-octen-3-one with anequivalent amount of 1-(dimethylamino)-1-penten-3-one,1-(dimethylamino)-1-hexen-3-one, 1-(dimethylamino)-1-hepten-3-one,1-(dimethylamino)-1-nonen-3-one or 1-(dimethylamino)-1-decen-3-one, then1,3-heptadien-5-one, 1,3-octadien-5-one, 1,3-nonadien-5-one,1,3-undecadien-5-one and 1,3-dodecadien-5-one are obtained,respectively.

EXAMPLE 39 3-(Dimethylamino)-1-decyn-5-one

A mixture of 1-(dimethylamino)-1-octen-3-one (4.0 g), described inExample 37, and lithiumacetylide-ethyleneamine (4.0 g) in dry dioxane(25 ml) is stirred at room temperature for 45 min. The mixture is addedto ice. The mixture is extracted with ether. The extract is dried (Na₂SO₄) and then evaporated. The residue is distilled to afford the titlecompound, b.p. 80° - 85° C.

In the same manner but replacing 1-(dimethylamino)-1-octen-3-one with anequivalent amount of 1-(dimethylamino)-1-penten-3-one,1-(dimethylamino)-1-hexen-3-one, 1-(dimethylamino)-1-hepten-3-one,1-(dimethylamino)-1-nonen-3-one or 1-(dimethylamino)-1-decen-3-one,described in Example 37, then 3-(dimethylamino)-1-heptyn-5-one,3-(dimethylamino)-1-octyn-5-one, 3-(dimethylamino)-1-nonyn-5-one,3-(dimethylamino)-1-undecyn-5-one and 3-(dimethylamino)-1-dodecyn-5-oneare obtained, respectively.

EXAMPLE 40 1,3-Decadien-5-one

To a solution of 3-(dimethylamino)-1-decyn-5-one (2.2 g) described inExample 39, in methanol (20 ml) p-toluenesulfonic acid (1 g) is added.The solution is allowed to stay at room temperature for 5 hr. thendiluted with ether. The organic layer is washed with water, dried(MgSO₄) and evaporated to dryness. Chromatographic purification of theresidue on 25 g silica gel with ether-hexane (1:4) affords3-decen-1-yn-5-one.

A solution of the latter compound (1.93 g) in hexane (20 ml) containingquinoline (1 ml) and Lindlar catalyst (100 mg) is hydrogenated at roomtemperature and atmospheric pressure. After the absorption of 296 ml ofhydrogen, the reaction mixture is filtered through diatomaceous earth,washed with 10% hydrochloric acid, then with water, dried and the hexaneevaporated to give the title compound, identical to the product ofExample 38.

In the same manner but replacing 3-(dimethylamino)-1-decyn-5-one with anequivalent amount of 3-(dimethylamino)-1-heptyn-5-one,3-(dimethylamino)-1-octyn-5-one, 3-(dimethylamino)-1-nonyn-5-one,3-(dimethylamino)-1-undecyn-5-one, or 3-(dimethylamino)-1-dodecyn-5-one,then 1,3-heptadien-5-one, 1,3-octadien-5-one, 1,3-nonadien-5-one,1,3-undecadien-5-one and 1,3-dodecadien-5-one are obtained,respectively.

EXAMPLE 41 Diethyltrans-2-(3-Oxo-1-octenyl)cyclopropane-1,1-dicarboxylate[VI, R² ═ H, R⁴ ═C₂ H₅ and (c) ═ (CH₂)₄ ]

To a solution of diethylbromomalonate (2.87 g) in absolute ethanol (3ml) is added simultaneously sodium ethoxide (from 276 mg sodium) inethanol (6 ml) and 1,3-decadien-5-one (1.9 g), described in Example 40,in ethanol (3 ml). The sodium ethoxide is added over a period of 20 min.and the dienone over a period of 10 minutes. The mixture is stirred at0° C for 3 hr., then at room temperature for 16 hr., acidified with 0.5ml of acetic acid and the sodium bromide is separated by filtration andwashed with benzene. Evaporation of the solvent affords the amideproduct, which is subject to chromatography on 350 g silica gel elutionwith ether-hexane (1:4) to give the title compound, nmr (CDCl₃) δ0.88(t, 3H), 4.18 (q, 4H), 6.22 (s, 1H), 6.28 (s, 1H).

In the same manner but replacing 1,3-decadien-5-one with an equivalentamount of 1,3-heptadien-5-one, 1,3-octadien-5-one, 1,3-nonadien-5-one,1,3-undecadien-5-one or 1,3-dodecadien-5-one, then diethyltrans-2-(3-oxo-1-pentenyl)cyclopropane-1,1-dicarboxylate, diethyltrans-2-(3-oxo-1-hexenyl)cyclopropane-1,1-dicarboxylate, diethyltrans-2-(3-oxo-1-heptenyl)-cyclopropane-1,1-dicarboxylate, diethyltrans-2-(3-oxo-1-nonenyl)-cyclopropane-1,1-dicarboxylate, and diethyltrans-2-(3-oxo-1-decenyl)-cyclopropane-1,1-dicarboxylate are obtainedrespectively.

Likewise the corresponding dimethyl and dipropyl esters of the abovecompounds of formula VI are obtained when diethylbromomalonate isreplaced by dimethyl or dipropyl bromomalonate, respectively, in theprocedure of this example.

EXAMPLE 42 Dimethyltrans-2-(3-Hydroxy-1-octenyl)cyclopropane-1,1-dicarboxylate [II, R² ═ H,R⁴ ═ CH₃, R⁵ ═ H and (c) ═ (CH₂)₄ ]

A solution of 5.5 g of sodium borohydride in 50 ml. of 95% ethanol isadded to a solution of the compound of formula VI, dimethyltrans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (35 g),described in Example 2. After 15 min. at room temperature the mixture iscooled in ice and rendered neutral by the addition of acetic acid. Wateris added and the mixture extracted with ethyl-acetate. The extract wasdried (Na₂ SO₄) and the evaporated. The residue is purified bychromatography on silica gel to afford the title compound, nmr (CDCl₃)δ0.90 (t, 3H), 2.33 (1H), 3.73 (s, 3H) 4.05 (m, 1H).

By following the procedure of Example 42 and utilizing the appropriatecompound of formula VI then other compounds of formula II (R⁵ ═ H) areprepared. Examples of such compounds of formula II are listed in TableII. In each case the compound of formula VI used as starting material isnoted by the Example in which it is prepared.

                                      TABLE II                                    __________________________________________________________________________           NO. OF EXAMPLE                                                                IN WHICH STARTING                                                                            PRODUCT: (PREFIX LISTED BELOW)CYCLO-                    EXAMPLE                                                                              MATERIAL IS PREPARED                                                                         PROPANE-1,1-DICARBOXYLATE                               __________________________________________________________________________    43      3             dimethyl trans-2-(3-hydroxy-                                                  1-pentenyl)                                             44      4             diethyl trans-2-(3-hydroxy-                                                   1-octenyl)                                              45      5             .sub.max.sup.film trans-2-(3-hydroxy-                                         1-heptenyl)                                             46      6             dimethyl trans-2-(3-hydroxy-                                                  1-nonenyl)                                              47      7             dimethyl trans-2-(3-hydroxy-                                                  1-decenyl)                                              48      8             dimethyl trans-2-(3-hydroxy-                                                  1,5-heptadienyl)                                        49      9             dimethyl trans-2-(3-hydroxy-                                                  1,5-octadienyl)                                         50     10             dimethyl trans-2-(3-hydroxy-                                                  1,5-nonadienyl)                                         51     11             dimethyl trans-2-(3-hydroxy-                                                  1,5-decadienyl)                                         52     12             dimethyl trans-3-methyl-2-                                                    (3-hydroxy-1-pentenyl)                                  53     13             dimethyl-trans-3-methyl-2-                                                    (3-hydroxy-1-hexenyl)                                   54     14             dimethyl-trans-3-methyl-2-                                                    (3-hydroxy-1-heptenyl)                                  55     15             dimethyl-trans-3-methyl-2-                                                    (3-hydroxy-1-octenyl)                                   56     16             dimethyl-trans-3-methyl-2-                                                    (3-hydroxy-1-nonenyl)                                   57     17             dimethyl-trans-3-methyl-2-                                                    (3-hydroxy-1-decenyl)                                   58     18             dimethyl trans-3-methyl-2-                                                    (3-hydroxy-1,5-heptadienyl)                             59     19             dimethyl trans-3-methyl-2-                                                    (3-hydroxy-1,5-octadienyl)                              60     20             dimethyl trans-3-methyl-2-                                                    (3-hydroxy-1,5-nonadienyl)                              61     21             dimethyl trans-3-methyl-2-                                                    (3-hydroxy-1,5-decadienyl)                              62     22             dimethyl trans-3-ethyl-2-                                                     (3-hydroxy-1-pentenyl)                                  63     23             diethyl trans-3-ethyl-2-                                                      (3-hydroxy-1-octenyl)                                   64     24             dimethyl trans-3-ethyl-2-                                                     (3-hydroxy-1-decenyl)                                   65     25             diethyl trans-3-ethyl-2-                                                      (3-hydroxy-1,5-heptadienyl)                             66     26             diethyl trans-3-ethyl-2-                                                      (3-hydroxy-1,5-octadienyl)                              67     27             dimethyl trans-3-propyl-2-                                                    (3-hydroxy-1-hexenyl)                                   68     28             dimethyl trans-3-propyl-2-                                                    (3-hydroxy-1-octenyl)                                   69     29             diethyl trans-3-isopropyl-2-                                                  (3-hydroxy-1-nonenyl)                                   70     30             dimethyl trans-3-isopropyl-2-                                                 (3-hydroxy-1,5-nonadienyl)                              71     31             dimethyl trans-3-propyl-2-                                                    (3-hydroxy-1,5-decadienyl)                              72     32             dimethyl trans-3-(acetoxymethyl)-                                             2-(3-hydroxy-1-heptenyl)                                73     33             diethyl trans-3-(acetoxymethyl)-                                              2-(3-hydroxy-1-octenyl),δmax/film 3600,                                 3500, 1730 cm.sup.-1                                    74     34             diethyl trans-3-(acetoxymethyl)-                                              2-(3-hydroxy-1-decenyl)                                 75     35             diethyl trans-3-(acetoxymethyl)                                               2-(3-hydroxy-1,5-heptadienyl)                           76     36             diethyl trans-3-(acetoxymethyl)-                                              2-(3-hydroxy-1,5-octadienyl)                            __________________________________________________________________________

EXAMPLE 77 Dimethyltrans-2-{3-[(Tetrahydropyran-2-yl)oxy]-1-octenyl}cyclopropane-1,1-dicarboxylate[II, R² ═ H, R⁴ ═ CH₃, R⁵ ═ tetrahydropyran-2-yl) and (c) ═ (CH₂)₄ ]

A solution of dimethyltrans-2-(3-hydroxy-1-octenyl)-cyclopropane-1,1-dicarboxylate (22.4g),described in Example 42, dihydropyran (80 ml, distilled over sodium) andp-toluenesulfonic acid monohydrate (300 mg) is allowed to stand at roomtemperature for 30 min. After adding a few ml of 10% Na₂ CO₃ solutionthe mixture is extracted with ether. The ether extract is washed withwater, dried (Na₂ SO₄) and evaporated. Purification of the residue bychromatography on silica gel gives the title compound.

In the same manner but using an equivalent amount of one of thecompounds of formula II (R⁵ ═ H), for example, the compounds listed inExample 43 to 76, instead of dimethyltrans-2-(3-hydroxy-1-octenyl)cyclopropane-1,1-dicarboxylate, then thecorresponding tetrahydropyranyl ether compound of formula II (R⁵ ═tetrahydropyranyl) is obtained, for example, the correspondingtetrahydropyranyl ether compounds of Examples 43 to 76, respectively.More specifically exemplified, in the same manner diethyltrans-3-(acetoxymethyl)-2-(3-hydroxy-1-octenyl)cyclopropane-1,1-dicarboxylate(Example 73) gives diethyltrans-3-(acetoxymethyl)-2-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}cyclopropane-1,1-dicarboxylate,γ_(max) ^(film) 1740, 1720 cm⁻¹, and dimethyltrans-3-methyl-2-(3-hydroxy-1,5-heptadienyl)cyclopropane-1,1-dicarboxylate(Example 58) gives dimethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-1,5-heptadienyl}cyclopropane-1,1-dicarboxylate.

EXAMPLE 78 7-Hydroxy-5-heptynoic Acid (XII, p = 3)

By following the procedure of A. I. Rachlin, et al., cited above,6-chloro-2-hexyn-1-ol is prepared by condensing propargyl alcoholtetrahydropyran-2-yl ether and the dihaloalkane of formula VIII,1-bromo-3-chloropropane, to give1-[(tetrahydropyran-2-yl)oxy]-6-chloro-2-hexyne, which is then convertedto the desired compound followed by hydrolysis in the presence ofsulfuric acid. The 6-chloro-2-hexyn-1-ol (280 g) is dissolved in ethanol(2.8 l) then water (560 ml) and potassium cyanide (290 g) is added andthe mixture stirred and refluxed for 20 hr. Potassium hydroxide (768 g)and water (500 ml) are added and the stirred mixture kept at reflux foran additional 20 hr. Methanol is evaporated and the water phase isacidified with concentrated HCl and extracted with ether for 2 days in acontinuous liquid-liquid extractor. The ether extract is dried (Na₂ SO₄)and concentrated to give the title compound, nmr (CDCl₃) δ4.22 (m, 2H),7.41 (broad, 2H).

EXAMPLE 79 Methyl 7-Bromo-5-heptynoate (XV, p = 3 and R ═ CH₃)

To a solution of 7-hydroxy-5-heptynoic acid (88. 2 g), described inExample 78, in anhydrous ether (300 ml) and pyridine (12 ml) is addeddropwise phosphorus tribromide (67.5 g) at 10° C. The solution isstirred at room temperature for 30 min. then cooled to 5° C and 10% HCl(120 ml) is added slowly. The organic layer is washed with water and 10%sodium carbonate, dried (Na₂ SO₄) and concentrated. The residue isdistilled under reduced pressure to give 7-bromo-5-heptynoic acid, b.p.146° C, 0.8 mm.

The latter compound is esterified in the following manner. The lattercompound (156 g) is dissolved in absolute methanol (1.5 l).p-Toluenesulfonic acid (78 g) is added to the solution which is thenheated at reflux for 2 hr. Thereafter the solvent is evaporated. Theresidue is dissolved in water and the aqueous solution extracted withbenzene. The extract is washed with 10% Na₂ CO₃ and then water untilneutral, dried (Na₂ SO₄) and concentrated. The residue is distilled togive the title compound, b.p. 70° - 80° C 0.2 mm.

The corresponding ethyl or other lower alkyl esters of the lattercompound are likewise prepared according to the preceding esterificationprocedure by replacing methanol with ethanol or an appropriatecorresponding lower alkanol, respectively.

Alternatively, the procedure of this example may be reversed whereby7-hydroxy-5-heptynoic acid is first subjected to the esterificationprocedure with methanol and p-toluenesulfonic acid, followed bytreatment of the resulting hydroxy ester XIV (p = 3 and R ═ CH₃) withphosphorus tribromide as described herein.

By following serially the procedures of Examples 78 and 79 but using thedihaloalkanes of formula VIII, 1-bromo-2-chloroethane or1-bromo-4-chlorobutane, instead of 1-bromo-4-chloropropane, then methyl6-bromo-4-hexynoate and methyl 8-bromo-6-octaynoiate are obtained,respectively.

Furthermore, an equivalent amount of the correspondingα-iodo-ω-chloroalkane used in place of the dihaloalkane of formula VIIin the serial application of the procedures of Examples 78 and 79 givesthe corresponding chloroester of the bromoester of formula XV; namely,1-chloro-2-iodoethane, 1-chloro-3-iodopropane and 1-chloro-4-iodobutaneyield methyl 6-chloro-4-hexynoate, methyl 7-chloro-5-heptynoate andmethyl 8-chloro-6-octynoate, respectively. These latter methyl estersmay be used in the manner described below for utilizing the bromoestersof formula XV.

EXAMPLE 80 Trimethyl 3-Heptyne-1,1,7-tricarboxylate (III; (a) ═ C.tbd.C,p = 3, R ═ CH₃ and R⁶ ═ CH₃)

Dimethyl malonate (39. 6 g, 0.3 mole) is added slowly with cooling andstirring to a solution of 6.9 g (0.3 atom) of sodium dissolved in 100 mlof absolute methanol and the mixture stirred for 15 min. The bromesterof formula XV, methyl 7-bromo-5-heptynoate (65.7 g, 0.3 mole), describedin Example 79, is added dropwise. The mixture is heated at reflux for 1hr., cooled and diluted with water. The mixture is extracted with ether.The ether extracts are dried (Na₂ SO₄) and concentrated. The residue isdistilled under reduced pressure, to give the title compound, b.p. 153°C/0.4 mm., nmr (CDCl₃) δ3.69, 3.78.

In the same manner but replacing methyl 7-bromo-5-heptynoate with anequivalent amount of methyl 6-bromo-4-hexynoate or methyl8-bromo-6-octanoate, trimethyl 3-hexyne-1,1,6-tricarboxylate andtrimethyl 3-octyne-1,1,8-tricarboxylate are obtained, respectively.

In the same manner but replacing methyl 7-bromo-5-heptynoate with anequivalent amount of methyl 6-bromo-4-hexenoate, methyl7-bromo-5-heptenaote, methyl 8-bromo-6-octenoate, methyl6-bromohexenoate, methyl 7-bromoheptanoate, or methyl 8-bromooctanoate,trimethyl 3-hexene-1,1,6-tricarboxylate, trimethyl3-heptene-1,1,7-tricarboxylate, trimethyl 3-octene-1,1,8-tricarboxylate,trimethyl hexane-1,1,6-tricarboxylate, trimethylheptane-1,1,7-tricarboxylate and trimethyl octane-1,1,8-tricarboxylateare obtained, respectively.

By using the corresponding ethyl or other lower alkyl ester analogs ofthe methyl ester starting materials noted above, the corresponding ethylor other lower alkyl esters of the methyl ester products, noted above,are obtained.

EXAMPLE 81 Trimethyl cis-3-Heptene-1,1,7-tricarboxylate (III, (a) ═CH═CH, p = 3, R ═ CH₃ and R⁶ ═ CH₃)

Trimethyl 3-heptyne-1,1,7-tricarboxylate (30.5 g), described in Example80, is hydrogenated in the presence of 1.0 g of Lindlar catalyst [Org.Syn., 46, 89 (1966)] in a solution of 100 ml of ethyl acetate and 1000ml of hexane. After 4 hr. and absorption of 740 ml of hydrogenationanother 1.0 g of catalyst is added. After a further 8 hr. an additional880 ml of hydrogen is absorbed. No further absorption of hydrogen isobserved. After filtering the filtrate is concentrated. The residue isdistilled under reduced pressure. The title compound has b.p. 140° -150° C/0.7 mm., nmr (CDCl₃) δ3.55 (1H), 5.41 (m, 2H), identical to thesame compound described in Example 80.

In the same manner but using trimethyl 3-hexyne-1,1,6-tricarboxylate ortrimethyl 3-octyne-1,1,8-tricarboxylate, trimethyl3-hexene-1,1,6-tricarboxylate and trimethyl3-octene-1,1,8-tricarboxylate, identical to the same compounds describedin Example 80, are obtained.

EXAMPLE 82 Dimethylcis,trans-3-(6-Carbomethoxy-2-hexenyl)-4-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate(IVa; (a) ═ CH═CH, p = 3, (c) ═ (CH₂)₄, R, R⁴ and R⁶ ═ CH₃ and R⁵ and R⁷═ H)

Procedure A [using compound II (R⁵ ═ tetrahydropyran-2-yl)]

To a mixture of the compound of formula II, dimethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}cyclopropane-1,1-dicarboxylate(20.4 g), described in Example 77, and the compound of formula III,trimethyl cis-3-heptene-1,1,7-tricarboxylate (15.08 g), described inExample 81, a solution of 1.27 g of sodium in 50 ml of methanol is addedat room temperature. The methanol is removed under slightly reducedpressure. The residue is heated at 135° - 140° C for 1 hr. while keepinga slightly reduced pressure in the reaction flask. Saturated NaClsolution is added and the mixture rendered neutral with acetic acid. Themixture is extracted with ether. The extract is dried (Na₂ SO₄) andconcentrated. Chromatography of the residue on silica gel yieldsdimethylcis,trans-3-(6-carbomethoxy-2-hexenyl)-4-{3-[tetrahydropyran-2-yl)oxy]-1-octenyl}-2-oxo-1,3-cyclopentanedicarboxylate,nmr (CDCl₃) δ0.90 (t, J = 6, 3H), 3.68-3.78 (3 H), 3.20 (2H), 4.20 (1H).

A solution of the latter compound (10.5 g) in 80 ml of methanol-water(9:1) and 1.0 g of p-toluenesulfonic acid monohydrate is left at roomtemperature for 15 min. and then rendered neutral with aqueous NaHCO₃.The methanol is evaporated and after addition of saturated NaCl, themixture is extracted with ether. The ether layer is dried (Na₂ SO₄).Evaporation of the solvent gives a residue, which on purification bychromatography on silica gel affords the title compound, nmr (CDCl₃)0.90 (t, J = 5, 3H), 3.68, 3.74 and 3.78 (3H), 4.15 (1H), 5.1-5.8 (m,1H).

Procedure B [using compound II (R⁵ ═ H)]

Sodium methoxide [from 0.5 g (0.022 atom) of sodium and 30 ml ofabsolute methanol] is added at room temperature to a mixture of 5.6 g(0.02 mole) of the compound of formula II, dimethyltrans-2-(3-hydroxy-1-octenyl)cyclopropane-1,1-dicarboxylate, describedin Example 42, and 5.4 g (0.02 mole) of the compound of formula III,trimethyl cis-3-heptene-1,1,7-tricarboxylate, described in Example 81,in 10 ml of absolute methanol. After refluxing for 2 hr. the methanol isremoved at reduced pressure and the residue adjusted to pH 6 with aceticacid. The mixture is extracted with ether. The ether extract is workedup in the same manner as described for the ether extract in procedure Aof this example. In this manner the title compound is obtained,identical to the product of procedure A.

By following the procedures A or B of Example 82 and using theappropriate compounds of formulae II and III as starting materials,other cyclopentanonetriesters of formulae IVa or IVb are prepared.Examples of such compounds of formula IV are listed in Tables III andIIIa together with the requisite starting materials. It is to be notedthat when procedure A is used the requisite starting material of formulaII is the corresponding tetrahydropyran-2-yl ether derivative of thecompound of formula II noted therein; the tetrahydropyran-2-yl etherbeing prepared by following the procedure described in Example 77.Preparation of the starting materials of formula III, i.e. triesters offormula III, is described in Examples 80 and 81.

                                      TABLE III                                   __________________________________________________________________________       NO. OF EXAMPLE                                                                IN WHICH STARTING                                                             MATERIAL OF  STARTING MATERIAL OF                                                                         PRODUCT: (PREFIX LISTED BELOW)-                   FORMULA II   FORMULA III    2-OXO-1,3-CYCLOPENTANEDI-                      EX.                                                                              IS DESCRIBED  (a) p R and R.sup.6                                                                         CARBOXYLATE                                    __________________________________________________________________________    83 43           C.tbd.C                                                                            2 CH.sub.3                                                                              dimethyl trans-3-(5-carbomethoxy-                                             2-pentynyl)-4-(3-hydroxy-1-                                                   pentenyl)                                      84 44           C.tbd.C                                                                            3 C.sub.2 H.sub.5                                                                       diethyl trans-3-(6-carboethoxy-                                               2-hexynyl)-4-(3-hydroxy-1-octenyl),                                           δ.sub.max.sup.film 3450, 1737, 1225                                     cm.sup.-1.                                     85 45           C.tbd.C                                                                            4 CH.sub.3                                                                              dimethyl trans-3-(7-carbomethoxy-                                             2-heptynyl)-4-(3-hydroxy-                                                     1-heptenyl)                                    86 46           CH═CH                                                                          2 CH.sub.3                                                                              dimethyl cis, trans-3-(5-                                                     carbomethoxy-2-pentenyl)-4-                                                   (3-hydroxy-1-nonenyl)                          87 47           CH═CH                                                                          3 CH.sub.3                                                                              dimethyl cis, trans-3-(6-                                                     carbomethoxy-2-hexenyl)-4-                                                    (3-hydroxy-1-decenyl)                          88 48           CH═CH                                                                          4 CH.sub.3                                                                              dimethyl cis, trans-3-(7-                                                     carbomethoxy-2-heptenyl)-4-                                                   (3-hydroxy-1,5-heptadienyl)                    89 49           CH.sub.2 CH.sub.2                                                                  2 CH.sub.3                                                                              dimethyl trans-3-(5-carbo-                                                    methoxypentyl)-4-(3-hydroxy-                                                  1,5-octadienyl)                                90 50           CH.sub.2 CH.sub.2                                                                  3 CH.sub.3                                                                              dimethyl trans-3-(6-carbo-                                                    methoxyhexyl)-4-(3-hydroxy-                                                   1,5-nonadienyl)                                91 51           CH.sub.2 CH.sub.2                                                                  4 CH.sub.3                                                                              dimethyl trans-3-(7-carbo-                                                    methoxyheptyl)-4-(3-hydroxy-                                                  1,5-decadienyl)                                92 52           C.tbd.C                                                                            2 CH.sub.3                                                                              dimethyl trans-3-(5-carbo-                                                    methoxy-2-pentynyl)-4-(3-hydroxy-                                             1-pentenyl)-5-methyl                           93 53           C.tbd.C                                                                            3 CH.sub.3                                                                              dimethyl trans-3-(6-carbo-                                                    methoxy-2-hexynyl)-4-                                                         (3-hydroxy-1-hexenyl)-5-methyl                 94 54           C.tbd.C                                                                            4 CH.sub.3                                                                              dimethyl trans-3-(7-carbo-                                                    methoxy-2-heptynyl)-4-(3-hydroxy-                                             1-heptenyl)-5-methyl                           95 55           CH═CH                                                                          2 CH.sub.3                                                                              dimethyl cis, trans-3-(5-carbo-                                               methoxy-2-pentenyl)-4-(3-hydroxy-                                             1-octenyl)-5-methyl                            96 56           CH═CH                                                                          3 CH.sub.3                                                                              dimethyl cis, trans-3-(6-carbo-                                               methoxy-2-hexenyl)-4-(3-hydroxy-                                              1-nonenyl)-5-methyl                            97 57           CH═CH                                                                          4 CH.sub.3                                                                              dimethyl cis, trans-3-(7-carbo-                                               methoxy-2-heptenyl)-4-(3-hydroxy-                                             -     1-decenyl)-5-methyl                      98 58           CH.sub.2 CH.sub.2                                                                  2 CH.sub.3                                                                              dimethyl trans, cis-3-(5-carbo-                                               methoxypentyl)-4-(3-hydroxy-                                                  1,5-heptadienyl)-5-methyl                      99 59           CH.sub.2 CH.sub.2                                                                  3 CH.sub.3                                                                              dimethyl trans, cis-3-(6-carbo-                                               methoxyhexyl)-4-(3-hydroxy-                                                   1,5-octadienyl)-5-methyl                       100                                                                              60           CH.sub.2 CH.sub.2                                                                  4 CH.sub.3                                                                              dimethyl trans, cis-3-(7-carbo-                                               methoxyheptyl)-4-(3-hydroxy-                                                  1,5-nonadienyl)-5-methyl                       101                                                                              61           C.tbd.C                                                                            2 CH.sub.3                                                                              dimethyl trans, cis-3-(5-carbo-                                               methoxy-2-pentynyl)-4-(3-hydroxy-                                             1,5-decadienyl)-5-methyl                       102                                                                              62           C.tbd.C                                                                            3 CH.sub.3                                                                              dimethyl trans, cis-3-(6-carbo-                                               methoxy-2-hexynyl)-4-(3-hydroxy-                                              1-pentenyl)-5-ethyl                            103                                                                              63           C.tbd.C                                                                            4 C.sub.2 H.sub.5                                                                       diethyl trans-3-(7-carboethoxy-                                               2-heptynyl)-4-(3-hydroxy-                                                     1-octenyl)-5-ethyl                             104                                                                              64           CH═CH                                                                          2 CH.sub.3                                                                              dimethyl cis, trans-3-(5-carbo-                                               methoxy-2-pentenyl)-4-(3-hydroxy-                                             1-decenyl)-5-ethyl                             105                                                                              65           CH═CH                                                                          3 C.sub.2 H.sub.5                                                                       diethyl cis, trans, cis-3-(6-                                                 carboethoxy-2-hexenyl)-4-                                                     (3-hydroxy-1,5-heptadienyl)-                                                  5-ethyl                                        106                                                                              66           CH═CH                                                                          4 C.sub.2 H.sub.5                                                                       diethyl cis, trans, cis-3-(7-                                                 carboethoxy-2-heptenyl)-4-                                                    (3-hydroxy-1,5-octadienyl)-                                                   5-ethyl                                        107                                                                              67           CH.sub.2 CH.sub.2                                                                  2 CH.sub.3                                                                              dimethyl trans-3-(5-carbo-                                                    methoxypentyl)-4-(3-hydroxy-                                                  1-hexenyl)-5-propyl                            108                                                                              68           CH.sub.2 CH.sub.2                                                                  3 CH.sub.3                                                                              dimethyl trans-3-(6-carbo-                                                    methoxyhexyl)-4-(3-hydroxy-                                                   1-octenyl)-5-propyl                            109                                                                              69           CH.sub.2 CH.sub.2                                                                  4 C.sub.2 H.sub.5                                                                       diethyl trans-3-(7-carboethoxy-                                               heptyl)-4-(3-hydroxy-1-nonenyl)-                                              5-isopropyl                                    110                                                                              70           C.tbd.C                                                                            2 CH.sub.3                                                                              dimethyl trans, cis-3-(5-carbo-                                               methoxy-2-pentynyl)-4-(3-hydroxy-                                             1,5-nonadienyl)-5-isopropyl                    111                                                                              71           C.tbd.C                                                                            3 CH.sub.3                                                                              dimethyl trans, cis-3-(6-carbo-                                               methoxy-2-hexynyl)-4-(3-hydroxy-                                              1,5-decadienyl)-5-propyl                       __________________________________________________________________________

                                      TABLE IIIa                                  __________________________________________________________________________       NO. OF EXAMPLE IN                                                             WHICH STARTING                                                                MATERIAL OF  STARTING MATERIAL                                                                          PRODUCT: (PREFIX LISTED BELOW)-5-                   FORMULA II   OF FORMULA III                                                                             (HYDROXYMETHYL)-2-OXO-1-CYCLO-                   EX.                                                                              IS DESCRIBED  (a) p R and R.sup.6                                                                       PENTANECARBOXYLIC ACID γ-LACTONE           __________________________________________________________________________    112                                                                              72           C.tbd.C                                                                            4 CH.sub.3                                                                            trans-3-carbomethoxy-3-(7-carbo-                                              methoxy-2-heptynyl)-4-(3-hydroxy-                                             1-heptenyl)                                      113                                                                              73           CH.sub.2 CH.sub.2                                                                  3 C.sub.2 H.sub.5                                                                     trans-3-carboethoxy-3-(6-carbo-                                               ethoxyhexyl)-4-(3-hydroxy-1-                                                  octenyl), δ.sub.max.sup.film 3500,                                      1770,                                                                         1730 cm.sup.-1.                                  114                                                                              74           CH═CH                                                                          3 C.sub.2 H.sub.5                                                                     cis, trans-3-carboethoxy-3-(6-                                                carboethoxy-2-hexenyl)-4-(3-                                                  hydroxy-1-decenyl)                               115                                                                              75           CH.sub.2 CH.sub.2                                                                  3 C.sub.2 H.sub.5                                                                     trans, cis-3-carboethoxy-3-(6-                                                carboethoxyhexyl)-4-(3-hydroxy-                                               1,5-heptadienyl)                                 116                                                                              76           CH.sub.2 CH.sub.2                                                                  4 C.sub.2 H.sub.5                                                                     trans, cis-3-carboethoxy-3-(7-                                                carboethoxyheptyl)-4-(3-hydroxy-                                              1,5-octadienyl)                                  __________________________________________________________________________

EXAMPLE 117trans,cis-7-[2-(3-Hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic Acid(I; (a) ═ CH═CH, p = 3, (b) ═ CH═CH, (c) ═ (CH₂)₄ and R, R¹ and R² ═ H)

The cyclopentanonetriester of formula IV, dimethylcis,trans-3-(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate(11.2 g), described in Example 82, is heated to reflux for 1 hr. in asolution of sodium hydroxide (13.4 g) in 80 ml of water and 110 ml ofmethanol. The mixture is cooled, adjusted to pH 5 with 2N HCl, dilutedwith saturated sodium chloride solution and extracted with ether. Theether extract is dried (Na₂ SO₄) and concentrated to yield the titlecompound as a mixture of C₁₅ epimers is separated by silica gelchromatography using hexane:chloroform:acetic acid: 10:20:1. The lesspolar epimer is designated epimer A, nmr (CDCl₃) δ1.05 (t, J = 5, 3H),4.20 (1H), 5.33-5.78 (1H), 6.38 (2H). The more polar epimer isdesignated epimer B, nmr (CDCl₃) δ1.05 (t, J = 5, 3H) 4.18 (1H),5.30-5.77 (1H), 6.74 (2H).

By following the procedure of Example 117 and using the appropriatecyclopentanonetriester of formula IV, for example those described inExamples 83 to 116, then other compounds of formula I in which R and R¹are hydrogen are obtained. Examples of such compounds of formula I arelisted in Table IV together with the requisite cyclopentanonetriesterstarting material, the latter compound being noted by the exampledescribing its preparation.

                                      TABLE IV                                    __________________________________________________________________________           No. of Example                                                                in which cyclo-                                                               pentanonetriester                                                             of formula IV is                                                       EXAMPLE                                                                              prepared    PRODUCT:                                                   __________________________________________________________________________    118    83       trans-6-[2-(3-hydroxy-1-pentenyl)-5-oxocyclopentyl]-                          4-hexynoic acid                                               119    84       trans-7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-                           5-heptynoic acid, δ.sub.max.sup.film 3475 and 1735                      cm.sup.-1                                                     120    85       trans-8-[2-(3-hydroxy-1-heptenyl)-5-oxocyclopentyl]-                          6-octynoic acid                                               121    86       trans,cis-6-[2-(3-hydroxy-1-nonenyl)-5-oxocyclo-                              pentyl]-4-hexenoic acid                                       122    87       trans,cis-7-[2-(3-hydroxy-1-decenyl)-5-oxocyclo-                              pentyl]-5-heptenoic acid                                      123    88       trans,cis,cis-8-[2-(3-hydroxy-1,5-heptadienyl)-                               5-oxocyclopentyl]-6-octenoic acid                             124    89       trans,cis,cis-6-[2-(3-hydroxy-1,5-octadienyl)-                                5-oxocyclopentyl]hexanoic acid                                125    90       trans,cis,cis-7-[2-(3-hydroxy-1,5-nonadienyl)-                                5-oxocyclopentyl]heptanoic acid                               126    91       trans,cis,cis-8-[2-(3-hydroxy-1,5-decadienyl)-                                5-oxocyclopentyl]octanoic acid                                127    92       trans-6-[2-(3-hydroxy-1-pentenyl)-3-methyl-                                   5-oxocyclopentyl]-4-hexynoic acid                             128    93       trans-7-[2-(3-hydroxy-1-hexenyl)-3-methyl-                                    5-oxocyclopentyl]-5-heptynoic acid                            129    94       trans-8-[2-(3-hydroxy-1-heptenyl)-3-methyl-                                   5-oxocyclopentyl]-6-octynoic acid                             130    95       trans,cis-6-[2-(3-hydroxy-1-octenyl)-3-methyl-                                5-oxocyclopentyl]-4-hexenoic acid                             131    96       trans,cis-7-[2-(3-hydroxy-1-nonenyl)-3-methyl-                                5-oxocyclopentyl]-5-heptenoic acid                            132    97       trans,cis-8-[2-(3-hydroxy-1-decenyl)-3-methyl-                                5-oxocyclopentyl]-6-octenoic acid                             133    98       trans,cis-6-[2-(3-hydroxy-1,5-heptadienyl)-                                   3-methyl-5-oxocyclopentyl]hexanoic acid                       134    99       trans,cis-7-[2-(3-hydroxy-1,5-octadienyl)-                                    3-methyl-5-oxocyclopentyl]heptanoic acid                      135    100      trans,cis-8-[ 2-(3-hydroxy-1,5-nonadienyl)-                                   3-methyl-5-oxocyclopentyl]octanoc acid                        136    101      trans,cis-6-[2-(3-hydroxy-1,5-decadienyl)-                                    3-methyl-5-oxocyclopentyl]-4-hexynoic acid                    137    102      trans-7-[2-(3-hydroxy-1-pentenyl)-3-ethyl-                                    5-oxocyclopentyl]5-heptynoic acid                             138    103      trans-8-[2-(3-hydroxy-1-octenyl)-3-ethyl-                                     5-oxocyclopentyl]-6-octynoic acid                             139    104      trans,cis-6-[2-(3-hydroxy-1-decenyl)-3-ethyl-                                 5-oxocyclopentyl]-4-hexenoic acid                             140    105      trans,cis,cis-7-[2-(3-hydroxy-1,5-heptadienyl)-                               3-ethyl-5-oxocyclopentyl]-5-heptenoic acid                    141    106      trans,cis,cis-8-[2-(3-hydroxy-1,5-octadienyl)-                                3-ethyl-5-oxocyclopentyl]-6-octenoic acid                     142    107      trans-6-[2-(3-hydroxy-1-hexenyl)-3-propyl-                                    5-oxocyclopentyl]hexanoic acid                                143    108      trans-7-[2-(3-hydroxy-1-octenyl)-3-propyl-                                    5-oxocyclopentyl]heptanoic acid                               144    109      trans-8-[2-(3-hydroxy-1-nonenyl)-3-isopropyl-                                 5-oxocyclopentyl]octanoic acid                                145    110      trans,cis-6-[2-(3-hydroxy-1,5-nonadienyl)-                                    3-isopropyl-5-oxocyclopentyl]-4-hexynoic acid                 146    111      trans,cis-7-[2-(3-hydroxy-1,5-decadienyl)-                                    3-propyl-5-oxocyclopentyl]-5-heptynoic acid                   147    112      trans-8-[2-(3-hydroxy-1-heptenyl)-3-(hydroxy-                                 methyl)-5-oxocyclopentyl-6-octynoic acid                      148    113      trans-7-[2-(3-hydroxy-1-octenyl)-3-(hydroxy-                                  methyl)-5-oxocyclopentyl]heptanoic acid,                                      δ.sub.max.sup.film                                                      3400 -3600, 1710 cm.sup.-1                                    149    114      trans,cis-7-[2-(3-hydroxy-1-decenyl)-3-(hydroxy-                              methyl)-5-oxocyclopentyl]-5-heptanoic acid                    150    115      trans,cis-7-[2-(3-hydroxy-1,5-heptadienyl)-                                   3-(hydroxymethyl)-5-oxocyclopentyl]heptanoic acid             151    116      trans,cis-8-[2-(3-hydroxy-1,5-octadienyl)-                                    3-(hydroxymethyl)-5-oxocyclopentyl]octanoic                   __________________________________________________________________________                    acid                                                      

EXAMPLE 152 Methyltrans,cis-7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoate (I;(a) ═ CH═CH, p = 3, (b) ═ CH═CH, (c) ═ (CH₂)₄, R ═ CH₃ and R¹ and R² ═H)

The compound of formula I,trans,cis-7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid(16.0 g), described in Example 117, is dissolved in 150 ml of absolutemethanol. Perchloric acid (5 to 10 drops) is added to the solution whichis kept at room temperature for 2 hr. Thereafter the mixture isconcentrated. The residue is diluted with water and shaken with ether.The ether layer is washed with 10% Na₂ CO₃ and then water until neutral,dried (MgSO₄) and concentrated to yield the title compound, γ_(max)^(CHCl).sbsp.3 1705 cm⁻¹.

In the same manner but using the appropriate choice of the compound offormula I and lower alkanol, then other corresponding esters of formulaI (R═lower alkyl) are prepared. For example, the choice oftrans-8-[2-(3-hydroxy-1-heptenyl)-5-oxocyclopentyl]-6-octynoic acid(Example 120) and ethanol, instead of the compound of formula I andmethanol in the procedure of this example gives ethyltrans-8-[2-(3-hydroxy-1-heptenyl)-5-oxocyclopentyl]-6-octynoate.Similarly the choice oftrans-7-[2-(3-hydroxy-1-octenyl)-3-(hydroxymethyl)-5-oxocyclopentyl]heptanoicacid (Example 148) and methanol gives methyltrans-7-[2-(3-hydroxy-1-octenyl)-3-(hydroxymethyl)-5-oxocyclopentyl]heptanoate,γ_(max) ^(film) 3420, 1730 cm⁻¹.

EXAMPLE 153 Methyltrans,cis-7-[2-(3-acetoxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoate

A solution of the compound of formula I, methyltrans,cis-7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoate (5g), described in Example 161, in 50 ml of pyridine and 50 ml of aceticanhydride is stirred at room temperature for 4 hr. The solution isdiluted with ice-water and extracted with ether. The ether is washedwith 10% H₂ SO₄, water 10% Na₂ CO₃ and water, dried (Na₂ SO₄) andevaporated to give the title compound.

In the same manner but using the appropriate choice of compound offormula I (R¹ ═H) and lower alkanoic anhydride, then other compounds offormula I (R═lower alkanoyl and if R² is CH₂ OR³ then R³ is loweralkanoyl) are prepared. For example the choice oftrans-8-[2-(3-hydroxy-1-nonenyl)-3-isopropyl-5-oxocyclopentyl]octanoicacid (Example 144) and propionic anhydride instead of the compound offormula I and acetic anhydride noted in the procedure of this Example,givetrans-8-[2-(3-propionoxy-1-nonenyl)-3-isopropyl-5-oxocyclopentyl]octanoicacid. Similarly, ethyltrans-8-[2-(3-hydroxy-1-heptenyl)-5-oxocyclopentyl]-6-octynoate (seeExample 161) and butyric anhydride gives ethyltrans-8-[2-(3-butyryloxy-1-heptenyl)-5-oxocyclopentyl]-6-octynate.

We claim:
 1. A compound of the formula ##STR9## in which (a) is C.tbd.C,p is an integer from 2 to 4, (b) is trans CH═CH, (c) is (CH₂)q wherein qis an integer from 1 to 6, R is hydrogen or lower alkyl, R¹ is hydrogenand R² is hydrogen or CH₂ OH. 2.trans-7-[2-(3-Hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptynoic acid asclaimed in claim 1.